Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation.

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

Microglial modulation through colony-stimulating factor-1 receptor inhibition attenuates demyelination.

Multiple sclerosis (MS) is one of the most common causes of progressive disability affecting young people with very few therapeutic options available for its progressive forms. Its pathophysiology involves demyelination and neurodegeneration apparently driven by microglial activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In the present work, we used microglial modulation through oral administration of brain-penetrant CSF-1R inhibitor BLZ945 in acute and chronic cuprizone (CPZ)-induced demyelination to evaluate preventive and therapeutic effects on de/remyelination and neurodegeneration. Our results show that BLZ945 induced a significant reduction in the number of microglia. Preventive BLZ945 treatment attenuated demyelination in the acute CPZ model, mainly in cortex and external capsule. In contrast, BLZ945 treatment in the acute CPZ model failed to protect myelin or foster remyelination in myelin-rich areas, which may respond to a loss in microglial phagocytic capacity and the consequent impairment in oligodendroglial differentiation. Preventive and therapeutic BLZ945 treatment promoted remyelination and neuroprotection in the chronic model. These results could be potentially transferred to the treatment of progressive forms of MS.